tbuckley/cabot-search huggingface dataset:
Abstract IA22: Molecular classes and landscape of drivers of intrahepatic and extrahepatic cholangiocarcinoma
Authors: Daniela Sia
Journal: Clinical Cancer Research (2022)

Abstract Cholangiocarcinoma (CCA) is an aggressive malignancy originating from the neoplastic transformation of the epithelial cells of the bile ducts, both intrahepatic (iCCA) and extrahepatic (eCCA), and among the fastest growing cancers in the United states. Therapeutic options for CCA patients at advanced stages are limited and palliative chemotherapy remains the main treatment option. Over the past decade, the application of next-generation sequencing has significantly impacted the management of CCA where clinically-relevant subgroups have been identified based on the recurrence of specific structural aberrations (i.e. FGFR2 fusions, IDH1 mutations) with important differences according to the anatomical site. These efforts have increased the molecular understanding of this disease and ultimately suggested that iCCA and eCCA may represent distinct entities. Thereby, increasing efforts have tried to generate molecular classifications specific for each subtype, although initial studies analyzed CCA samples regardless of their anatomic site of origin. We will review current knowledge of the molecular landscape and immunogenomic classifications proposed to date for iCCA and eCCA. Citation Format: Daniela Sia. Molecular classes and landscape of drivers of intrahepatic and extrahepatic cholangiocarcinoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA22.
Abstract PO012: In silico drug repurposing identifies mebendazole as a treatment option for chemoresistant hepatoblastoma
Authors: Qian Li, Salih Demir, Xuanwen Bao, Alexandra Wagner, Yanxin Fan, Stefano Cairo, Roland Kappler
Journal: Clinical Cancer Research (2022)

Abstract Resistance to conventional chemotherapy remains a huge challenge in the clinical management and treatment of hepatoblastoma, the most common liver tumor of childhood. The in silico repurposing of drugs with known pharmacokinetics and safety profiles, which have been approved for other indications, represents a promising strategy to identify new drugs effective in chemoresistant hepatoblastoma. In this study, we integrated RNA sequencing-derived gene expression data into the pharmacologic perturbation prediction tool Connectivity Map (CMap) and identified the clinical widely used anthelmintic drug mebendazole as a putative drug to circumvent chemoresistance in hepatoblastoma. Consequently, we experimentally validated the efficacy of mebendazole in permanent and patient-derived xenograft cell lines that are resistant to cisplatin, the therapeutic backbone of hepatoblastoma treatment. Viability assays clearly indicated a potent reduction of tumor cell growth upon mebendazole treatment in a dose-dependent manner. In contrast, similar mebendazole concentrations had little inhibitory effect on the growth of normal neonatal and adult skin fibroblasts. The combination of mebendazole and cisplatin revealed a strong synergistic effect, which was comparable to the one seen with cisplatin and doxorubicin (cardiotoxic), the current standard treatment for high-risk hepatoblastoma patients. Moreover, mebendazole treatment resulted in reduced colony formation capability, induction of apoptosis, and cell cycle arrest of hepatoblastoma cells. Immunofluorescent staining of alpha-tubulin showed that mebendazole causes blockage of microtubule formation and subsequent RNA sequencing analyses confirmed the transcriptional downregulation of tubulins as the major mode of action of mebendazole treatment. Most importantly, mebendazole significantly reduced tumor growth in a subcutaneous xenograft transplantation mouse model. In conclusion, our results strongly support the clinical use of mebendazole as a replacement for doxorubicin in the treatment of chemoresistant hepatoblastoma. This could potentially not only improve outcome but also reduce severe long-term side effects. Citation Format: Qian Li, Salih Demir, Xuanwen Bao, Alexandra Wagner, Yanxin Fan, Stefano Cairo, Roland Kappler. In silico drug repurposing identifies mebendazole as a treatment option for chemoresistant hepatoblastoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr PO012.
Abstract IA20: Combination therapies including checkpoint inhibitors in HCC: the dawn of a new era
Authors: Richard S. Finn
Journal: Clinical Cancer Research (2022)

Abstract After a decade of stalled progress in the medical management of advanced HCC we have seen rapid progress in improving survival for patients with advanced HCC. We have gone from incremental improvements with sequencing multi-kinase inhibitors to significant gains with immunotherapy-based combinations. Arguably, the success of combinations is driven by the increased response rates seen with this approach as compared to the challenges seen with single agent checkpoint inhibitors. Until biomarkers of response are identified, the continued development of new combinations will still be driven an all-comers approach, with the empiric addition of new agents to already established doublets. These new combinations will likely benefit from lessons learned in other diseases where immune checkpoint inhibitors have been used for much longer periods of time (melanoma, lung cancer). The challenge though, is when we look at progress in these other diseases, the next combination to move things forward is yet to be determined, whether in the front-line setting, or after progression on IO. Ongoing translational studies are offering insights into the mechanisms by which we are seeing increased activity with combinations, but the clinical utility of these data have not yet been determined. In the lecture we will review the data as it stands today and offer thoughts on the next generation of studies with systemic therapy in HCC. Citation Format: Richard S. Finn. Combination therapies including checkpoint inhibitors in HCC: the dawn of a new era [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA20.
Abstract PR03: Pretreatment immune cell composition and checkpoint ligand expression define the response to immunotherapy in advanced HCC: a study using single-cell sequencing
Authors: Sarah Cappuyns, Gino Philips, Vincent Vandecaveye, Chris Verslype, Eric Van Cutsem, Diether Lambrechts, Jeroen Derkervel
Journal: Clinical Cancer Research (2022)

Abstract The novel combination of atezolizumab/bevacizumab has demonstrated unprecedented response rates in a subgroup of advanced hepatocellular carcinoma (aHCC) patients. In order to understand why only a subset of aHCC patients respond to immunotherapy targeting the PD-1/PD-L1 axis, we subjected pre-treatment tissue biopsies from 31 aHCC patients, with mainly non-viral etiologies, to simultaneous single-cell transcriptome (scRNAseq) and T-cell receptor (scTCRseq) sequencing, providing an integrative view of the tumor-microenvironment of aHCC (n=91 169 cells). The therapeutic targets, PD-1 and PD-L1 are expressed in tumor-infiltrating T- cells versus myeloid cells and tumor cells, respectively. Myeloid cells in tumors responding to immunotherapy (according to mRECIST) express significantly higher levels of PD-L1 (p=0.014) compared to non-responders and this is driven by pro-inflammatory PD-L1 expressing CXCL10+ macrophages, involved in T-cell recruitment. In contrast, non-responding tumors are infiltrated by immature CX3CR1+ macrophages and CCR2+ ‘monocyte-like’ macrophages (p=0.009 and p=0.01, respectively). Interestingly, the composition of tumor-infiltrating T-cells did not differ significantly between patient groups. However, responding tumors were characterized by a more clonal baseline T-cell receptor repertoire (p=0.007). Single-cell T-cell receptor sequencing revealed that this clonality was present in activated, effector T-cells, while non-responders had a higher proportion of non-clonal T-cells (p=0.01) concentrated within naïve and memory-like T-cell phenotypes. In conclusion, this is the first and largest aHCC cohort to correlate single-cell sequencing data with clinical outcomes. Prior to treatment, differences in abundancy and ligand expression in small clusters of immune cells as well as difference in baseline T-cell clonality drive response to checkpoint inhibition in aHCC. Citation Format: Sarah Cappuyns, Gino Philips, Vincent Vandecaveye, Chris Verslype, Eric Van Cutsem, Diether Lambrechts, Jeroen Derkervel. Pretreatment immune cell composition and checkpoint ligand expression define the response to immunotherapy in advanced HCC: a study using single-cell sequencing [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr PR03.
Computer copilots for endoscopic diagnosis
Authors: James A. Diao, Joseph C. Kvedar
Journal: npj Digital Medicine (2022)

Artificial intelligence (AI) tools for endoscopy are now entering clinical practice after demonstrating substantial improvements to polyp detection on colonoscopy. As this technology continues to mature, efforts to develop and validate a new frontier of possibilities—including diagnostic classification, risk stratification, and clinical outcomes assessment—are now underway. In npj Digital Medicine, scientists from Cosmo AI/Linkverse and collaborators report an extension to the first FDA-cleared AI tool for colonoscopy that goes beyond polyp detection to enable video-based diagnostic characterization.
Wearable accelerometer-derived physical activity and incident disease
Authors: Shaan Khurshid, Lu-Chen Weng, Victor Nauffal, James P. Pirruccello, Rachael A. Venn, Mostafa A. Al-Alusi, Emelia J. Benjamin, Patrick T. Ellinor, Steven A. Lubitz
Journal: npj Digital Medicine (2022)

Physical activity is regarded as favorable to health but effects across the spectrum of human disease are poorly quantified. In contrast to self-reported measures, wearable accelerometers can provide more precise and reproducible activity quantification. Using wrist-worn accelerometry data from the UK Biobank prospective cohort study, we test associations between moderate-to-vigorous physical activity (MVPA) - both total MVPA minutes and whether MVPA is above a guideline-based threshold of ≥150 min/week-and incidence of 697 diseases using Cox proportional hazards models adjusted for age, sex, body mass index, smoking, Townsend Deprivation Index, educational attainment, diet quality, alcohol use, blood pressure, anti-hypertensive use. We correct for multiplicity at a false discovery rate of 1%. We perform analogous testing using self-reported MVPA. Among 96,244 adults wearing accelerometers for one week (age 62 ± 8 years), MVPA is associated with 373 (54%) tested diseases over a median 6.3 years of follow-up. Greater MVPA is overwhelmingly associated with lower disease risk (98% of associations) with hazard ratios (HRs) ranging 0.70-0.98 per 150 min increase in weekly MVPA, and associations spanning all 16 disease categories tested. Overall, associations with lower disease risk are enriched for cardiac (16%), digestive (14%), endocrine/metabolic (10%), and respiratory conditions (8%) (chi-square p < 0.01). Similar patterns are observed using the guideline-based threshold of ≥150 MVPA min/week. Some of the strongest associations with guideline-adherent activity include lower risks of incident heart failure (HR 0.65, 95% CI 0.55-0.77), type 2 diabetes (HR 0.64, 95% CI 0.58-0.71), cholelithiasis (HR 0.61, 95% CI 0.54-0.70), and chronic bronchitis (HR 0.42, 95% CI 0.33-0.54). When assessed within 456,374 individuals providing self-reported MVPA, effect sizes for guideline-adherent activity are substantially smaller (e.g., heart failure HR 0.84, 95% CI 0.80-0.88). Greater wearable device-based physical activity is robustly associated with lower disease incidence. Future studies are warranted to identify potential mechanisms linking physical activity and disease, and assess whether optimization of measured activity can reduce disease risk.
The Effect of Macular Hole Duration on Surgical Outcomes
Authors: Declan C. Murphy, Mo Al-Zubaidy, Noemi Lois, Neil Scott, David H. Steel, Jinfeng Qu, Mingwei Zhao, Srinivas Sadda, Sreekumar Manasa, Divya Agarwal, Atul Kumar, Prateek Kakkar, Serge Bourgault, Eric Tourville, Raul Velez-Montoya, Sergio E. Hernandez-Da Mota, J. Abel Ramirez-Estudillo, Jerzy Nawrocki, Zofia Anna Nawrocka, Clemens Lange, James Bainbridge, David Yorston, Mark Alberti, Morten la Cour, Ulrik Christensen, Kwok Kwan Ho Alvin
Journal: Ophthalmology (2022)

trials
LRP1 is a neuronal receptor for α-synuclein uptake and spread
Authors: Kai Chen, Yuka A. Martens, Axel Meneses, Daniel H. Ryu, Wenyan Lu, Ana Caroline Raulin, Fuyao Li, Jing Zhao, Yixing Chen, Yunjung Jin, Cynthia Linares, Marshall Goodwin, Yonghe Li, Chia-Chen Liu, Takahisa Kanekiyo, David M. Holtzman, Todd E. Golde, Guojun Bu, Na Zhao
Journal: Molecular Neurodegeneration (2022)

The aggregation and spread of α-synuclein (α-Syn) protein and related neuronal toxicity are the key pathological features of Parkinson's disease (PD) and Lewy body dementia (LBD). Studies have shown that pathological species of α-Syn and tau can spread in a prion-like manner between neurons, although these two proteins have distinct pathological roles and contribute to different neurodegenerative diseases. It is reported that the low-density lipoprotein receptor-related protein 1 (LRP1) regulates the spread of tau proteins; however, the molecular regulatory mechanisms of α-Syn uptake and spread, and whether it is also regulated by LRP1, remain poorly understood.We established LRP1 knockout (LRP1-KO) human induced pluripotent stem cells (iPSCs) isogenic lines using a CRISPR/Cas9 strategy and generated iPSC-derived neurons (iPSNs) to test the role of LRP1 in α-Syn uptake. We treated the iPSNs with fluorescently labeled α-Syn protein and measured the internalization of α-Syn using flow cytometry. Three forms of α-Syn species were tested: monomers, oligomers, and pre-formed fibrils (PFFs). To examine whether the lysine residues of α-Syn are involved in LRP1-mediated uptake, we capped the amines of lysines on α-Syn with sulfo-NHS acetate and then measured the internalization. We also tested whether the N-terminus of α-Syn is critical for LRP1-mediated internalization. Lastly, we investigated the role of Lrp1 in regulating α-Syn spread with a neuronal Lrp1 conditional knockout (Lrp1-nKO) mouse model. We generated adeno-associated viruses (AAVs) that allowed for distinguishing the α-Syn expression versus spread and injected them into the hippocampus of six-month-old Lrp1-nKO mice and the littermate wild type (WT) controls. The spread of α-Syn was evaluated three months after the injection.We found that the uptake of both monomeric and oligomeric α-Syn was significantly reduced in iPSNs with LRP1-KO compared with the WT controls. The uptake of α-Syn PFFs was also inhibited in LRP1-KO iPSNs, albeit to a much lesser extent compared to α-Syn monomers and oligomers. The blocking of lysine residues on α-Syn effectively decreased the uptake of α-Syn in iPSNs and the N-terminus of α-Syn was critical for LRP1-mediated α-Syn uptake. Finally, in the Lrp1-nKO mice, the spread of α-Syn was significantly reduced compared with the WT littermates.We identified LRP1 as a key regulator of α-Syn neuronal uptake, as well as an important mediator of α-Syn spread in the brain. This study provides new knowledge on the physiological and pathological role of LRP1 in α-Syn trafficking and pathology, offering insight for the treatment of synucleinopathies.
Association between fat mass and mortality: analysis of Mendelian randomization and lifestyle modification
Authors: Jinbo Hu, Xiangjun Chen, Jun Yang, Edward Giovannucci, Dong Hoon Lee, Wenjin Luo, Qingfeng Cheng, Lilin Gong, Zhihong Wang, Qifu Li, Shumin Yang
Journal: Metabolism (2022)
Gut and obesity/metabolic disease: Focus on microbiota metabolites
Authors: Ke Lin, Lixin Zhu, Li Yang
Journal: MedComm (2022)

Abstract Obesity is often associated with the risk of chronic inflammation and other metabolic diseases, such as diabetes, cardiovascular disease, and cancer. The composition and activity of the gut microbiota play an important role in this process, affecting a range of physiological processes, such as nutrient absorption and energy metabolism. The active gut microbiota can produce a large number of physiologically active substances during the process of intestinal metabolism and reproduction, including short‐chain/long‐chain fatty acids, secondary bile acids, and tryptophan metabolites with beneficial effects on metabolism, as well as negative metabolites, including trimethylamine N‐oxide, delta‐valerobetaine, and imidazole propionate. How gut microbiota specifically affect and participate in metabolic and immune activities, especially the metabolites directly produced by gut microbiota, has attracted extensive attention. So far, some animal and human studies have shown that gut microbiota metabolites are correlated with host obesity, energy metabolism, and inflammation. Some pathways and mechanisms are slowly being discovered. Here, we will focus on the important metabolites of gut microbiota (beneficial and negative), and review their roles and mechanisms in obesity and related metabolic diseases, hoping to provide a new perspective for the treatment and remission of obesity and other metabolic diseases from the perspective of metabolites.
Organic Small Molecule Contrast Agent for Targeted Photoacoustic Imaging of Patient‐Derived Brain Tumors
Authors: Min Wu, Kai Xiao, Xingang Liu, Yudan Yang, Gousheng Song, Gelei Xiao, Qing Liu, Jian Yuan, Bin Liu
Journal: Advanced Healthcare Materials (2022)

Abstract Traditional glioblastoma (GBM) cell lines do not maintain the heterogeneity of the original tumor, cell interactions, and therapy response, thus limiting their investigation in GBM theranostics. Herein, a kind of GBM tumor‐targeting nanoparticles (NPs) TCFNP@iRGD are designed and constructed, which are generated by photoacoustic (PA) contrast agent 2‐(3‐cyano‐4,5,5‐trimethylfuran‐2(5H)‐ylidene) malononitrile (TCF)‐OH through facile nanoprecipitation and decorated with an active targeting ligand iRGD. Their potential in GBM detection via PA imaging on glioma patient‐derived cells intracranial xenograft models is evaluated for the first time. Excellent tumor‐specific PA mapping performance of GBM is realized by TCFNP@iRGD, demonstrating its promising potential in the clinical diagnosis of GBM.
Manganese‐Based Nanozymes: Preparation, Catalytic Mechanisms, and Biomedical Applications
Authors: Minglu Tang, Zhaocong Zhang, Tiedong Sun, Bin Li, Zhiguang Wu
Journal: Advanced Healthcare Materials (2022)

Manganese (Mn) has attracted widespread attention due to its low-cost, nontoxicity, and valence-rich transition. Various Mn-based nanomaterials have sprung up and are employed in diverse fields, particularly Mn-based nanozymes, which combine the physicochemical properties of Mn-based nanomaterials with the catalytic activity of natural enzymes, and are attracting a surge of research, especially in the field of biomedical research. In this review, the typical preparation strategies, catalytic mechanisms, advances and perspectives of Mn-based nanozymes for biomedical applications are systematically summarized. The application of Mn-based nanozymes in tumor therapy and sensing detection, together with an overview of their mechanism of action is highlighted. Finally, the prospective directions of Mn-based nanozymes from five perspectives: innovation, activity enhancement, selectivity, biocompatibility, and application broadening are discussed.
Trem2 deletion enhances tau dispersion and pathology through microglia exosomes
Authors: Bing Zhu, Yan Liu, Spring Hwang, Kailey Archuleta, Huijie Huang, Alex Campos, Rabi Murad, Juan Piña-Crespo, Huaxi Xu, Timothy Y. Huang
Journal: Molecular Neurodegeneration (2022)

Alzheimer's disease (AD) is a neurodegenerative disorder that manifests sequential Aβ and tau brain pathology with age-dependent onset. Variants in the microglial immune receptor TREM2 are associated with enhanced risk of onset in sporadic Alzheimer's disease (AD). While recent studies suggest TREM2 dysfunction can aggravate tau pathology, mechanisms underlying TREM2-dependent modulation of tau pathology remains elusive.Here, we characterized differences in progressive tau spreading from the medial entorhinal cortex (MEC) to the hippocampus in wildtype (WT) and Trem2 knockout (KO) mice by injection of AAV-P301L tau into the MEC, and correlated changes in hippocampal tau histopathology with spatial and fear memory. We also compared effects of intraneuronal dispersion between cultured microglia and neurons using a microfluidic dispersion assay, analyzed differences in microglial tau trafficking following uptake, and quantified exosomal tau secretion and pathogenicity from purified WT and Trem2 KO exosomes.Trem2 deletion in mice (Trem2 KO) can enhance tau spreading from the medial entorhinal cortex (MEC) to the hippocampus, which coincides with impaired synaptic function and memory behavior. Trem2 deletion in microglia enhances intraneuronal dispersion of tau in vitro between neuronal layers cultured in a microfluidic chamber, and the presence of exosome inhibitors can significantly reduce tau in exosomes and extracellular media from tau-loaded microglia. Although microglial Trem2 deletion has no effect on tau uptake, Trem2 deletion enhances distribution to endosomal and cellular pre-exosomal compartments following internalization. Trem2 deletion has little effect on exosome size, however, proteomic analysis indicates that Trem2 deletion can modulate changes in the microglial proteomic landscape with tau and LPS/ATP treatment conditions associated with exosome induction. Furthermore, exosomes from Trem2 KO microglia show elevated tau levels, and feature enhanced tau-seeding capacity in a tau FRET reporter line compared to exosomes from WT microglia.Together, our results reveal a role for Trem2 in suppressing exosomal tau pathogenicity, and demonstrates that Trem2 deletion can enhance tau trafficking, distribution and seeding through microglial exosomes.
R-CEOP as first-line treatment for anthracycline-ineligible patients with diffuse large B-cell lymphoma
Authors: Diana Al-Sarayfi, Frederik O. Meeuwes, Müjde Durmaz, Djamila E. Issa, Rolf E. Brouwer, Aart Beeker, Anna van Rhenen, Pim G. N. J. Mutsaers, Lara H. Böhmer, Marjolein W. M. van der Poel, Liane te Boome, Tom van Meerten, Martine E. D. Chamuleau, Josée M. Zijlstra, Mirian Brink, Marcel Nijland
Journal: Blood Cancer Journal (2022)
Optical genome mapping refines cytogenetic diagnostics, prognostic stratification and provides new molecular insights in adult MDS/AML patients
Authors: Estelle Balducci, Sophie Kaltenbach, Patrick Villarese, Eugénie Duroyon, Loria Zalmai, Chloé Friedrich, Felipe Suarez, Ambroise Marcais, Didier Bouscary, Justine Decroocq, Rudy Birsen, Michaëla Fontenay, Marie Templé, Chantal Brouzes, Aurore Touzart, Thomas Steimlé, Agata Cieslak, Ludovic Lhermitte, Carole Almire, Nicolas Chapuis, Olivier Hermine, Vahid Asnafi, Olivier Kosmider, Lucile Couronné
Journal: Blood Cancer Journal (2022)